CN109824782A - 抗cd19抗体和muc1抗原肽的偶联物及其应用 - Google Patents
抗cd19抗体和muc1抗原肽的偶联物及其应用 Download PDFInfo
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- CN109824782A CN109824782A CN201910065210.1A CN201910065210A CN109824782A CN 109824782 A CN109824782 A CN 109824782A CN 201910065210 A CN201910065210 A CN 201910065210A CN 109824782 A CN109824782 A CN 109824782A
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Abstract
本发明提供一种抗CD19抗体和MUC1抗原肽的偶联物及其应用,所述偶联物包括抗CD19抗体重链,以及偶联有MUC1抗原肽的抗CD19抗体轻链即抗CD19抗体轻链‑MUC1;所述抗CD19抗体重链的氨基酸序列为SEQ ID NO:1所示的序列;所述抗CD19抗体轻链‑MUC1的氨基酸序列为SEQ ID NO:2所示的序列。所述偶联物与靶向MUC1的T淋巴细胞联合给药,可以获得同时靶向MUC1和CD19的治疗效果,对MUC1和CD19双抗原同时表达的肿瘤细胞具有较强的杀伤作用。
Description
技术领域
本发明涉及基因修饰细胞及肿瘤治疗技术领域,尤其涉及一种抗CD19抗体和MUC1抗原肽的偶联物及其应用。
背景技术
CAR-T疗法,全称为Chimeric Antigen Receptor T-Cell Immunotherapy,嵌合抗原受体T细胞免疫疗法。其主要原理是,从癌症病人身上分离免疫T细胞,利用基因工程技术为T细胞引入一个能够识别肿瘤细胞并同时激活T细胞的嵌合抗体,也就是制备CAR-T细胞,再将扩增好的CAR-T细胞回输到病人体内,通过免疫疗法对抗癌细胞。CAR-T的结构按照所处位置分为胞外区、跨膜区、胞内区三部分。胞外区又可以分为胞外铰链区(促进抗原受体与肿瘤抗原的结合)和肿瘤相关抗原结合区(scFv,用于识别并结合肿瘤特异性抗原),选择不同的肿瘤标志物作为抗原以杀伤不同的肿瘤细胞;跨膜区起到固定CAR作用;胞内区分为T细胞活化区(提供T细胞活化的第一信号,激活T细胞的增殖信号通路)和共刺激区(提供T细胞活化的第二信号,维持T细胞的生存时间),不同信号分子的选择对构建成的CAR-T细胞增殖分化、活性、因子分泌起到关键性作用。
与传统的肿瘤治疗策略相比,CAR-T细胞对肿瘤细胞的杀伤精准度高,而且不依赖于MHC(主要组织相容性复合体)的限制性。近年来,在B细胞淋巴瘤等血液恶性肿瘤的治疗中取得了积极的进展。除了血液系统肿瘤中的应用,研究者也将此项技术积极应用于实体肿瘤的治疗,如神经母细胞瘤、胶质瘤、胰腺癌等。
主要的成功案例集中在特异性靶向CD19分子的CAR-T。CD19是正常和恶性B淋巴细胞特异性表面蛋白,在B细胞的发育、增殖和分化以及恶性转化中发挥重要作用。因CD19在B淋巴细胞表达的特异性和恶性肿瘤表达的广泛性,使其成为一个颇具潜力的B淋巴细胞恶性肿瘤免疫治疗的分子靶点从而受到极大的关注。截至目前,全球共有2种CAR-T产品获批上市,靶点均为CD19,分别是来自诺华的Kymriah(tisagenlecleucel)(CTL019)和Kite制药的Yescarta(KTE-C19),它们分别用于治疗儿童和年轻成人(2~25岁)的急性淋巴细胞白血病和特定类型大B细胞淋巴瘤。
Mucin 1是膜结合型粘蛋白家族成员,简称MUC1。在正常情况下,MUC1呈低水平表达在乳腺,胰腺,胃肠道,呼吸道及泌尿生殖道的上皮细胞的近管腔面,不能被机体免疫系统识别,其表达特点为极性表达,顶端分布,糖基化丰富。在大多数腺癌、血液系恶性肿瘤中MUC1呈异常过表达,可通过调控多个信号通路调节细胞恶性转化,是促进肿瘤发生与发展的重要癌基因。由于MUC1在肿瘤细胞中的表达糖基化不全,并失去极性,遍布于整个细胞表面,容易被抗体识别,因此,MUC1蛋白也是CAR-T细胞抗肿瘤治疗的一个理想靶点。
发明内容
本发明提供了一种抗CD19抗体和MUC1抗原肽的偶联物,将其与靶向MUC1的T淋巴细胞联合给药,可以获得同时靶向MUC1和CD19的治疗效果,对MUC1和CD19双抗原同时表达的肿瘤细胞具有较强的杀伤作用。
本发明还提供了编码所述偶联物的核酸。
包含所述核酸的表达载体也属于本发明的保护范围。
本发明还提供了一种病毒,包含所述的表达载体。
本发明还提供了所述核酸、或所述表达载体或所述病毒的用途,用于制备抗CD19抗体和MUC1抗原肽的偶联物。
本发明还提供了所述偶联物、所述核酸、所述病毒在制备同时靶向MUC1和CD19的治疗肿瘤的药物组合中的应用。
本发明还提供了一种治疗肿瘤的药物组合,对MUC1和CD19双抗原同时表达的肿瘤细胞具有较强的杀伤作用。
本发明提供的抗CD19抗体和MUC1抗原肽的偶联物,
所述偶联物包括抗CD19抗体重链与抗CD19抗体轻链-MUC1;
所述抗CD19抗体轻链-MUC1为偶联有MUC1抗原肽的抗CD19抗体轻链;
所述抗CD19抗体重链的氨基酸序列为SEQ ID NO:1所示的序列;
所述抗CD19抗体轻链-MUC1的氨基酸序列为SEQ ID NO:2所示的序列。
本发明还提供了编码所述的偶联物的核酸,包括编码所述抗CD19抗体重链的核苷酸和编码所述抗CD19抗体轻链-MUC1的核苷酸,其中,编码所述抗CD19抗体重链的核苷酸为SEQ ID NO:3所示的序列,编码所述CD19抗体轻链-MUC1的核苷酸为SEQ ID NO:4所示的序列。
本发明提供的包含所述核酸的表达载体可以是慢病毒质粒,例如pGreen puro。
本发明提供的一种治疗肿瘤的药物组合,包括所述的偶联物与靶向MUC1的T淋巴细胞,所述靶向MUC1的T淋巴细胞的表面表达一种嵌合抗原受体,所述嵌合抗原受体包括如下的顺序连接的胞外结合区,铰链区和胞内信号区:
特异性识别MUC1蛋白的SCFV(即MUC1SCFV),IgD,CD28–OX40–CD3ζ。
在本发明的一个具体实施方式中,所述嵌合抗原受体具有SEQ ID NO:5所示的氨基酸序列;其对应的核苷酸序列为SEQ ID NO:6。
在本发明的另一个具体实施方式中,所述肿瘤是MUC1和CD19阳性的肿瘤。
本发明方案具有以下优点:
1)所述抗CD19抗体和MUC1抗原肽的偶联物可以通过慢病毒感染T淋巴细胞扩增后纯化获得,制备方法简单。
2)所述抗CD19抗体和MUC1抗原肽的偶联物与靶向MUC1的T淋巴细胞联合给药,可以获得同时靶向MUC1和CD19的治疗效果,对MUC1和CD19双抗原同时表达的肿瘤细胞具有较强的杀伤作用。
3)所述抗CD19抗体和MUC1抗原肽的偶联物可以作为一种开关,能可控地启动靶向MUC1的T淋巴细胞对CD19阳性肿瘤的杀伤作用或放大靶向MUC1的T淋巴细胞对MUC1和CD19双阳性表达肿瘤的杀伤作用。
附图说明
图1是本发明中抗CD19抗体和MUC1抗原肽的偶联物触发的靶向MUC1的T淋巴细胞对CD19阳性肿瘤细胞具有杀伤作用的设计示意图。
图2是本发明中所述嵌合抗原受体(即Anti MUC1CAR)结构示意图。
图3本发明提供的治疗肿瘤的药物组合对MUC1和CD19双阳小鼠的治疗效果。
图4本发明提供的治疗肿瘤的药物组合对CD19阳性小鼠的治疗效果。
图5本发明提供的治疗肿瘤的药物组合对MUC1阳性小鼠的治疗效果。
图6是慢病毒表达载体pGreen puro的结构示意图。
具体实施方式
实施例1抗CD19抗体和MUC1抗原肽的偶联物的制备
1.合成和扩增
1)合成编码抗CD19抗体重链的核苷酸序列(SEQ ID NO:3),以及编码所述CD19抗体轻链-MUC1的核苷酸序列(SEQ ID NO:4),均由苏州泓迅生物科技有限公司合成;
2)将SEQ ID NO:3,SEQ ID NO:4扩增后,分别克隆到慢病毒表达载体pGreen puro(购自爱迪基因(Add gene)公司)中,pGreen puro的结构示意图如图6所示,SEQ ID NO:3,SEQ ID NO:4通过酶切位点BamHI和EcoRI连到载体里,分别获得重组慢病毒载体1,重组慢病毒载体2,经酶切鉴定获得了重组载体。步骤2)中的扩增与克隆步骤均可采用本领域常规实验条件进行完成,这对于本领域技术人员来说是可以实现的。
2.慢病毒的包装
本实施例包装慢病毒具体步骤如下:
1)用含10%FBS的1640培养基培养293T细胞;然后将293T细胞以3x 105/cm2的密度传至直径15cm的培养皿中培养20h,保证转染时细胞汇合度为80-90%;用不含血清的1640培养基换液,备用;
2)取两个EP管,分别在两个EP管中加入1ml 1640培养基;将重组慢病毒载体pGreen puro(即重组慢病毒载体1或重组慢病毒载体2)与pMDLg PRRE、pRSV-Rev和pMD2.G质粒按照摩尔比1:1:1:1在EP管1中混匀;在EP管2中加入150ul Lipo2000,混匀放置5min;将EP管2中混有lipo2000的1640培养基加入含有质粒的EP管1中,混匀得到混合液,室温放置20min;
3)然后将所述混合液逐滴加入上述制备的293T细胞的培养皿中,继续培养4h后,用含10%FBS的1640培养基更换培养液,继续培养48h后收集293T细胞的上清用于病毒纯化。
3.慢病毒的纯化
将293T细胞的上清用0.22μm过滤膜过滤,滤液收集在50ml超滤管中,3000g/min下离心45min;将剩余的浓缩液转移至EP管,放-80℃保存备用,获得含有重组慢病毒1(含有SEQ ID NO:3)或重组慢病毒2(含有SEQ ID NO:4)的浓缩液。
4.抗CD19抗体和MUC1抗原肽的偶联物的制备
利用纯化的重组慢病毒1和重组慢病毒2同时感染293T细胞,用含10%FBS的RPMI1640完全培养基培养4x106的293T细胞,加入纯化后的150MOI的重组慢病毒1和150MOI的重组慢病毒2,37℃,培养16h,然后更换为含10%FBS的RPMI 1640完全培养基,继续培养48h,使抗CD19抗体的重链和偶联MUC1肽段的抗CD19抗体的轻链在293T细胞中表达并组装,之后通过protein G(购自碧云天(P5034-1mg))纯化,得到抗CD19抗体和MUC1抗原肽的偶联物,经测序鉴定抗CD19抗体和MUC1抗原肽的偶联物具有本申请设计的氨基酸序列。
实施例2靶向MUC1的T淋巴细胞的制备
1.CD8+T淋巴细胞的分离
A、人全血倒入50ml离心管,室温700g离心20分钟(普通离心)。
B、弃上清,在沉淀中加DPBS至50ml。
C:分别取25ml上述液体加到20ml人淋巴细胞分离液(购自北京索莱宝科技有限公司),将离心管室温离心800g 15分钟。
D:取白膜层细胞,加入DPBS,补足至50ml。
E:离心600g 10分钟,弃上清液,得外周血单个核细胞PBMC。
F:采用CD8+T细胞磁珠分选试剂盒(购自德国美天旎)分选CD8+T细胞。
2.重组慢病毒3的制备,其制备过程与实施例1中重组慢病毒1类似,不同之处在于,使用SEQ ID NO:6代替SEQ ID NO:3,SEQ ID NO:6为编码所述嵌合抗原受体的核苷酸序列,所述嵌合抗原受体具有SEQ ID NO:5所示的氨基酸序列(即SCFV–IgD–CD28–OX40–CD3ζ)。
3.靶向MUC1的T淋巴细胞的制备
用含10%胎牛血清(购自Gibco-BRL)的RPMI 1640完全培养基(RPMI 1640购自Gibco-BRL,添加胎牛血清后即为RPMI 1640完全培养基)培养CD8+T细胞。
第一天:加入抗CD3单克隆抗体(购自北京同立海源生物科技有限公司)对CD8+T细胞进行活化;
第三天:将活化的CD8+T细胞分为实验组和对照组
1)实验组,在4x106个活化的CD8+T细胞中加入150MOI的重组慢病毒3(含有AntiMUC1CAR即SEQ ID NO:6);
2)对照组,不做处理;
16h后将培养基更换为含有50IU/ml重组人IL-2的RPMI 1640完全培养基(IL-2购自北京同立海源生物科技有限公司),继续培养10-20天,然后观察T淋巴细胞生长情况。
结果显示:细胞在感染病毒后,能够形成典型的增殖克隆团。
第十四天,将实验组CD8+T细胞,以600g的离心力离心10min,弃尽上清以收集CD8+T细胞沉淀;再用PBS溶液重悬CD8+T细胞,并将CD8+T细胞调整密度为1x 107个/ml;将100μl的CD8+T细胞置于EP管,加入10μl FITC标记小鼠抗人CD8单克隆抗体(购自BD公司)和10μlPE标记的羊抗鼠F(ab)2抗体(购自Coulter公司);4℃孵育30min,PBS溶液洗涤2次,上流式细胞仪检测,所述嵌合抗原受体正确表达。
实施例3本发明提供的治疗肿瘤的药物组合在体内治疗肿瘤效果验证
一、MUC1和CD19双阳小鼠的治疗效果
在20只裸鼠(6周龄,体重18~20g,购自广东省医学实验动物中心)右腋下皮下注射5x 106Raji细胞(MUC1和CD19双阳性表达,购自ATCC),观察小鼠是否出现肿瘤,待肿瘤长到60mm3大小,将其随机分为4组。
1)对照组(对照/Raji),尾静脉注射生理盐水200ul/次,每周2次;
2)T细胞治疗组(T细胞/Raji),分别尾静脉注射没有经过病毒感染的CD8+T细胞1×107个/次,每周2次;
3)靶向MUC1的T淋巴细胞治疗组(Anti MUC1CAR-T细胞/Raji),分别尾静脉注射实施例2制备的靶向MUC1的T淋巴细胞1×107个/次,每周2次;
4)药物组合治疗组(开关-Anti MUC1CAR-T细胞/Raji):尾静脉注射实施例2制备的靶向MUC1的T淋巴细胞1×107个/次,每周2次;每次注射完细胞6h后给药抗CD19抗体和MUC1抗原肽的偶联物,给药剂量为0.5mg/kg裸鼠体重。
统计100天内小鼠生存状态,做生存率曲线,实验结果如图3所示,可以看出,与对照组和T细胞组比较,靶向MUC1的T淋巴细胞(即Anti MUC1CAR-T细胞)延长了MUC1和CD19双阳性表达的肿瘤的荷瘤小鼠的生存期,抗CD19抗体和MUC1抗原肽的偶联物(即开关)能放大靶向MUC1的T淋巴细胞对MUC1和CD19双阳性表达肿瘤的杀伤作用,小鼠生存期显著延长。图1是本发明中抗CD19抗体和MUC1抗原肽的偶联物触发的靶向MUC1的T淋巴细胞对CD19阳性 肿瘤细胞具有杀伤作用的设计示意图。
二、CD19阳性小鼠的治疗效果
在20只裸鼠(6周龄,体重18~20g,购自广东省医学实验动物中心)右腋下皮下注射5x 106采用siRNA沉默MUC1表达的Raji细胞(即Raji-MUC1siRNA),观察小鼠是否出现肿瘤,待肿瘤长到60mm3大小,将其随机分为4组。
1)对照组(对照/Raji-MUC1siRNA),尾静脉注射生理盐水200ul/次,每周2次;
2)T细胞治疗组(T细胞/Raji-MUC1siRNA),分别尾静脉注射没有经过病毒感染的CD8+T细胞1×107个/次,每周2次;
3)靶向MUC1的T淋巴细胞治疗组(Anti MUC1CAR-T细胞/Raji-MUC1siRNA),分别尾静脉注射实施例2制备的靶向MUC1的T淋巴细胞1×107个/次,每周2次;
4)药物组合治疗组(开关-Anti MUC1CAR-T细胞/Raji-MUC1siRNA):尾静脉注射实施例2制备的靶向MUC1的T淋巴细胞1×107个/次,每周2次;每次注射完细胞6h后给药抗CD19抗体和MUC1抗原肽的偶联物,给药剂量为0.5mg/kg裸鼠体重。
统计100天内小鼠生存状态,做生存率曲线,实验结果如图4所示,可以看出,在MUC1被siRNA沉默的情况下,与对照组和T细胞组比较,靶向MUC1的T淋巴细胞组小鼠的生存期没有显著变化;只有添加抗CD19抗体和MUC1抗原肽的偶联物(即开关)之后,靶向MUC1的T淋巴细胞才能对CD19阳性肿瘤细胞具有杀伤作用,从而延长小鼠的生存期。
三、MUC1阳性小鼠的治疗效果
在20只裸鼠(6周龄,体重18~20g,购自广东省医学实验动物中心)右腋下皮下注射5x 106采用siRNA沉默CD19表达的Raji细胞(即Raji-CD19siRNA),观察小鼠是否出现肿瘤,待肿瘤长到60mm3大小,将其随机分为4组。
1)对照组(对照/Raji-CD19siRNA),尾静脉注射生理盐水200ul/次,每周2次;
2)T细胞治疗组(T细胞/Raji-CD19siRNA),分别尾静脉注射没有经过病毒感染的CD8+T细胞1×107个/次,每周2次;
3)靶向MUC1的T淋巴细胞治疗组(Anti MUC1CAR-T细胞/Raji-CD19siRNA),分别尾静脉注射实施例2制备的靶向MUC1的T淋巴细胞1×107个/次,每周2次;
4)药物组合治疗组(开关-Anti MUC1CAR-T细胞/Raji-CD19siRNA):尾静脉注射实施例2制备的靶向MUC1的T淋巴细胞1×107个/次,每周2次;每次注射完细胞6h后给药抗CD19抗体和MUC1抗原肽的偶联物,给药剂量为0.5mg/kg裸鼠体重。
统计100天内小鼠生存状态,做生存率曲线,实验结果如图5所示,可以看出,在CD19被siRNA沉默的情况下,与对照组和T细胞组比较,靶向MUC1的T淋巴细胞延长了MUC1表达的肿瘤的荷瘤小鼠的生存期;即使添加了抗CD19抗体和MUC1抗原肽的偶联物(即开关),也未能放大靶向MUC1的T淋巴细胞对仅有MUC1表达肿瘤的杀伤作用。
序列表
<110> 深圳市芥至和生物科技有限公司
<120> 抗CD19抗体和MUC1抗原肽的偶联物及其应用
<130> CNCNP201811696
<160> 6
<170> PatentIn version 3.5
<210> 1
<211> 450
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗CD19 抗体重链的氨基酸序列
<400> 1
Met Glu Val Lys Leu Gln Glu Ser Gly Pro Gly Leu Val Ala Pro Ser
1 5 10 15
Gln Ser Leu Ser Val Thr Cys Thr Val Ser Gly Val Ser Leu Pro Asp
20 25 30
Tyr Gly Val Ser Trp Ile Arg Gln Pro Pro Arg Lys Gly Leu Glu Trp
35 40 45
Leu Gly Val Ile Trp Gly Ser Glu Thr Thr Tyr Tyr Asn Ser Ala Leu
50 55 60
Lys Ser Arg Leu Thr Ile Ile Lys Asp Asn Ser Lys Ser Gln Val Phe
65 70 75 80
Leu Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Ile Tyr Tyr Met
85 90 95
Ala Lys His Tyr Tyr Tyr Gly Gly Ser Tyr Ala Met Asp Tyr Trp Gly
100 105 110
Gln Gly Thr Ser Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser
115 120 125
Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
130 135 140
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
145 150 155 160
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
165 170 175
Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
180 185 190
Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
195 200 205
Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys
210 215 220
Asp Lys Thr His Thr Cys Pro Pro Cys Met Ala Pro Pro Val Ala Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Lys Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro His Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Gln His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 2
<211> 259
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 抗CD19 抗体轻链- MUC1的氨基酸序列
<400> 2
Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro Gln Ala His Gly
1 5 10 15
Val Thr Ser Ala Pro Asp Thr Arg Pro Ala Pro Gly Ser Thr Ala Pro
20 25 30
Pro Ala His Gly Val Thr Ser Ala Gly Gly Gly Gly Ser Asp Ile Gln
35 40 45
Met Thr Gln Thr Thr Ser Ser Leu Ser Ala Ser Leu Gly Asp Arg Val
50 55 60
Thr Ile Ser Cys Arg Ala Ser Gln Asp Ile Ser Lys Tyr Leu Asn Trp
65 70 75 80
Tyr Gln Gln Lys Pro Asp Gly Thr Val Lys Leu Leu Ile Tyr His Thr
85 90 95
Ser Arg Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
100 105 110
Gly Thr Asp Tyr Ser Leu Thr Ile Ser Asn Leu Glu Gln Glu Asp Ile
115 120 125
Ala Thr Tyr Phe Cys Gln Gln Gly Asn Thr Leu Pro Tyr Thr Phe Gly
130 135 140
Gly Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val
145 150 155 160
Phe Ile Phe Pro Pro Ser Asp Glu Gln Ser Lys Ser Gly Thr Ala Ser
165 170 175
Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln
180 185 190
Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val
195 200 205
Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Met Ser Thr Leu
210 215 220
Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu
225 230 235 240
Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn Arg
245 250 255
Gly Glu Cys
<210> 3
<211> 1350
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码所述抗CD19 抗体重链的核苷酸
<400> 3
atggaagtga agctgcagga gagcggccca ggactggtgg ctccttctca gagcctgtca 60
gtgacttgca ccgtgtccgg agtgtctctg ccagactacg gagtgtcttg gatcagacag 120
cctcctagaa agggactcga gtggctggga gtgatttggg gcagcgagac cacctactac 180
aacagcgccc tgaagagcag gctgaccatc atcaaggaca acagcaagag ccaggtgttc 240
ctgaagatga acagcctgca gaccgacgac accgccatct actactgcgc caagcactac 300
tactacggcg gcagctacgc catggactat tggggacagg gcacaagcgt gacagtgtct 360
agcgccagca ccaagggacc tagcgtgttt cctctggccc cttctagcaa gtctaccagc 420
ggaggaacag cagctctggg ttgtctggtg aaggactact tccccgagcc agtgaccgtg 480
tcttggaata gcggagccct gaccagcgga gtgcacacat ttccagccgt gctgcagagc 540
agcggactgt atagcctgag cagcgtggtg accgtgcctt cttcttctct gggcacccag 600
acctacatct gcaacgtgaa ccacaagccc agcaacacca aggtggacaa gaaggtggag 660
cccaagtctt gcgacaagac ccacacttgc cctccttgtc cagctcctcc agtggcaggt 720
cctagcgtgt ttctgttccc ccccaagcct aaggacaccc tgatgatcag ccggacccca 780
gaagtgactt gcgtggtggt ggacgtgtcc cacgaagacc ccgaggtcaa gttcaattgg 840
tacgtggacg gagtggaggt gcacaacgct aagaccaagc ccagggagga gcagtacaac 900
agcacctaca gggtggtgtc cgtgctgaca gtgctgcacc aggattggct gaacggcaag 960
gagtacaagt gcaaggtgtc caacaagggc ctgcccagca gcatcgagaa gaccatcagc 1020
aaggccaagg gccagcctag agaacctcag gtgtacaccc tgcccccttc tagagacgag 1080
ctgaccaaga accaggtgtc cctgacttgc ctcgtgaagg gcttctaccc cagcgatatc 1140
gccgtggagt gggaatctaa cggtcagcca gagaacaact acaagaccac ccccccagtg 1200
ctggacagcg acggcagctt cttcctgtac agcaagctga ccgtggacaa aagccgctgg 1260
cagcagggca acgtgttctc ttgcagcgtg atgcacgagg ccctgcacaa ccactacacc 1320
cagaagagcc tgagcctgag cccaggaaag 1350
<210> 4
<211> 780
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码所述抗CD19 抗体轻链- MUC1的核苷酸
<400> 4
atgcctgata ccagacccgc cccaggatct acagctcctc cagctcacgg agtgacaagc 60
gccccagata ccagaccagc tccaggatct acagcccctc cagctcacgg agtgacatca 120
gccggaggag gaggaagcga tatccagatg acccagacaa caagcagcct gagcgcctct 180
ctgggcgaca gagtgaccat ctcttgcagg gccagccagg acatcagcaa gtacctgaat 240
tggtaccagc agaagccaga cggcaccgtg aagctgctga tctaccacac cagccggctg 300
cacagcggag tgcctagcag attcagcggc agcggaagcg gcacagatta cagcctgacc 360
atcagcaacc tggagcagga ggacatcgcc acctacttct gccagcaggg caacaccctg 420
ccttacacat ttggcggcgg caccaagctg gagatcaaga gaaccgtggc cgctcctagc 480
gtgttcatct tccctcccag cgacgagcag ctgaaaagcg gaacagccag cgtcgtctgc 540
ctgctgaaca acttctaccc cagggaggcc aaggtccagt ggaaggtgga caacgctctg 600
cagagcggca actctcagga gagcgtgaca gagcaggaca gcaaggacag cacctacagc 660
ctgagcagca cactgaccct gagcaaagcc gactacgaga agcacaaggt gtacgcttgc 720
gaagtgaccc accagggact gtctagccca gtgaccaaga gcttcaaccg aggcgagtgc 780
<210> 5
<211> 564
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 嵌合抗原受体
<400> 5
Glu Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Met Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Asn Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ser Pro Glu Lys Gly Leu Glu Trp Val
35 40 45
Ala Glu Ile Arg Leu Lys Ser Asn Asn Tyr Ala Thr His Tyr Ala Glu
50 55 60
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Ser Ser
65 70 75 80
Val Tyr Leu Gln Met Asn Asn Leu Arg Ala Glu Asp Thr Gly Ile Tyr
85 90 95
Tyr Cys Thr Phe Gly Asn Ser Phe Ala Tyr Trp Gly Gln Gly Thr Thr
100 105 110
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
115 120 125
Gly Gly Gly Ser Asp Ile Val Val Thr Gln Glu Ser Ala Leu Thr Thr
130 135 140
Ser Pro Gly Glu Thr Val Thr Leu Thr Cys Arg Ser Ser Thr Gly Ala
145 150 155 160
Val Thr Thr Ser Asn Tyr Ala Asn Trp Val Gln Glu Lys Pro Asp His
165 170 175
Leu Phe Thr Gly Leu Ile Gly Gly Thr Asn Asn Arg Ala Pro Gly Val
180 185 190
Pro Ala Arg Phe Ser Gly Ser Leu Ile Gly Asp Lys Ala Ala Leu Thr
195 200 205
Ile Thr Gly Ala Gln Thr Glu Asp Glu Ala Ile Tyr Phe Cys Ala Leu
210 215 220
Trp Tyr Ser Asn His Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
225 230 235 240
Leu Gly Ser Glu Thr Phe Thr Cys Phe Val Val Gly Ser Asp Leu Lys
245 250 255
Asp Ala His Leu Thr Trp Glu Val Ala Gly Lys Val Pro Thr Gly Gly
260 265 270
Val Glu Glu Gly Leu Leu Glu Arg His Ser Asn Gly Ser Gln Ser Gln
275 280 285
His Ser Arg Leu Thr Leu Pro Arg Ser Leu Trp Asn Ala Gly Thr Ser
290 295 300
Val Thr Cys Thr Leu Asn His Pro Ser Leu Pro Pro Gln Arg Leu Met
305 310 315 320
Ala Leu Arg Glu Pro Ala Ala Gln Ala Pro Val Lys Leu Ser Leu Asn
325 330 335
Leu Leu Ala Ser Ser Asp Pro Pro Glu Ala Ala Phe Trp Val Leu Val
340 345 350
Val Val Gly Gly Val Leu Ala Cys Tyr Ser Leu Leu Val Thr Val Ala
355 360 365
Phe Ile Ile Phe Trp Val Arg Ser Lys Arg Ser Arg Leu Leu His Ser
370 375 380
Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His
385 390 395 400
Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg
405 410 415
Arg Asp Gln Arg Leu Pro Pro Asp Ala His Lys Pro Pro Gly Gly Gly
420 425 430
Ser Phe Arg Thr Pro Ile Gln Glu Glu Gln Ala Asp Ala His Ser Thr
435 440 445
Leu Ala Lys Ile Arg Val Lys Phe Ser Arg Ser Ala Glu Pro Pro Ala
450 455 460
Tyr Gln Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg
465 470 475 480
Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu
485 490 495
Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn
500 505 510
Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met
515 520 525
Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly
530 535 540
Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala
545 550 555 560
Leu Pro Pro Arg
<210> 6
<211> 1692
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 编码嵌合抗原受体的核苷酸序列
<400> 6
gaagtgcagc tgcagcagtc aggaggagga ctggtgcagc caggaggctc tatgaagctg 60
tcttgcgtgg ccagcggctt taccttcagc aactactgga tgaattgggt ccggcagagc 120
ccagagaaag gactcgagtg ggtggcagag atccggctga agagcaacaa ctacgccacc 180
cactacgccg aaagcgtgaa gggcaggttc accatcagca gggacgacag caagagcagc 240
gtgtacctgc agatgaacaa cctgagggcc gaggacaccg gcatctacta ttgcaccttc 300
ggcaattcct tcgcctattg gggccaggga accacagtga cagtgtctag cggcggagga 360
ggatctggag gaggaggaag cggaggagga ggaagcgata tcgtggtgac ccaggagagc 420
gctctgacaa caagcccagg cgagacagtg accctgactt gcagaagcag cacaggagcc 480
gtgaccacca gcaactacgc caattgggtg caggagaagc ccgaccatct gttcaccgga 540
ctgatcggcg gcacaaacaa cagagcccca ggagtgccag ccagattcag cggatctctg 600
atcggcgata aggccgctct gaccatcacc ggagcccaga cagaagacga ggccatctac 660
ttctgcgccc tctggtacag caaccattgg gtgttcggcg gcggcacaaa actgacagtg 720
ctgggcagcg agaccttcac ttgcttcgtc gtgggcagcg atctgaagga cgctcatctg 780
acttgggagg tggccggcaa agtgcctaca ggaggagtgg aagagggact gctggagaga 840
cacagcaacg gctctcagag ccagcactct aggctgaccc tgcccagaag cctgtggaat 900
gccggaacca gcgtgacttg caccctgaat cacccttctc tgcctcccca gagactgatg 960
gctctgagag aaccagcagc tcaggctcca gtgaagctgt ccctgaacct gctggctagc 1020
agcgatcctc cagaagccgc cttttgggtg ctggtggtcg tgggaggagt gctggcttgt 1080
tacagcctgc tggtgaccgt ggccttcatc atcttttggg tccggagcaa gcggagcaga 1140
ctgctgcaca gcgactacat gaacatgacc cccagaagac caggccctac cagaaagcac 1200
taccagccct acgcccctcc tagagacttc gccgcctaca ggagcagaag ggaccagaga 1260
ctgcctccag acgctcacaa gcctccagga ggcggcagct ttagaacacc tatccaggag 1320
gagcaggccg acgctcattc taccctggcc aagatccgcg tgaagttcag cagaagcgcc 1380
gagcctccag cttatcagca gggccagaac cagctgtaca acgagctgaa cctgggcagg 1440
agagaggaat acgacgtgct ggacaagagg aggggcagag atcccgagat gggaggcaag 1500
cccagaagaa agaaccccca ggagggcctg tacaacgagc tgcagaagga caagatggcc 1560
gaggcctaca gcgagattgg catgaagggc gagagaagga ggggcaaagg ccacgacgga 1620
ctgtatcagg gcctgtctac cgccaccaag gatacctacg acgctctgca catgcaggct 1680
ctgcctccta ga 1692
Claims (10)
1.抗CD19抗体和MUC1抗原肽的偶联物,其特征在于,
所述偶联物包括抗CD19抗体重链,以及抗CD19抗体轻链-MUC1;
所述抗CD19抗体轻链-MUC1为偶联有MUC1抗原肽的抗CD19抗体轻链;
所述抗CD19抗体重链的氨基酸序列为SEQ ID NO:1所示的序列;
所述抗CD19抗体轻链-MUC1的氨基酸序列为SEQ ID NO:2所示的序列。
2.编码权利要求1所述的偶联物的核酸。
3.如权利要求2所述的核酸,其特征在于,包括编码所述抗CD19抗体重链的核苷酸与编码所述抗CD19抗体轻链-MUC1的核苷酸,
编码所述抗CD19抗体重链的核苷酸为SEQ ID NO:3所示的序列;
编码所述抗CD19抗体轻链-MUC1的核苷酸为SEQ ID NO:4所示的序列。
4.一种表达载体,其特征在于,其包含权利要求2或3所述的核酸。
5.如权利要求4所述的表达载体,其特征在于,所述表达载体来源于慢病毒质粒。
6.一种病毒,其特征在于,其包含权利要求4或5所述的表达载体。
7.权利要求2或3所述的核酸、或权利要求4或5所述的表达载体或权利要求6所述的病毒的用途,其特征在于,用于制备抗CD19抗体和MUC1抗原肽的偶联物。
8.一种治疗肿瘤的药物组合,其特征在于,包括权利要求1所述的偶联物与靶向MUC1的T淋巴细胞,所述靶向MUC1的T淋巴细胞的表面表达一种嵌合抗原受体,所述嵌合抗原受体包括如下的顺序连接的胞外结合区,铰链区和胞内信号区:
特异性识别MUC1蛋白的SCFV,IgD,CD28–OX40–CD3ζ。
9.根据权利要求8所述的药物组合,其特征在于,所述嵌合抗原受体具有SEQ ID NO:5所示的氨基酸序列。
10.根据权利要求8所述的药物组合,其特征在于,所述肿瘤是MUC1和CD19阳性的肿瘤。
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